Cytomorphology review of 100 newly diagnosed lower-risk MDS patients in the European LeukemiaNet MDS (EUMDS) registry reveals a high inter-observer concordance

Objectives To examine contemporary survival patterns in the general population of patients diagnosed with chronic myeloid leukaemia (CML), and to identify patient groups with less than optimal outcomes. Design Prospective population-based cohort. Setting The UK's Haematological Malignancy Research Network (catchment population 3.6 million, with >2000 new haematological malignancies diagnosed annually). Participants All patients newly diagnosed with CML, from September 2004 to August 2011 and followed up to 31 March 2013. Main outcome measure Incidence and survival. Results With a median diagnostic age of 59 years, the CML age standardised (European) incidence was 0.9/100 000 (95% CIs 0.8 to 0.9), 5-year overall survival was 78.9% (72.3 to 84.0) and 5-year relative survival 88.6% (81.0 to 93.3). The efficacy of treatment across all ages was clearly demonstrated; the relative survival curves for those under 60 and over 60 years being closely aligned. Survival findings were similar for men and women, but varied with deprivation; the age and sex adjusted HR being 3.43 (1.89 to 6.22) for deprivation categories 4–5 (less affluent) versus 1–3 (more affluent). None of these differences were attributable to the biological features of the disease. Conclusions When therapy is freely provided, population-based survival for CML is similar to that reported in clinical trials, and age loses its prognostic significance. However, although most of the patients with CML now experience close to normal lifespans, those living in more deprived areas tend to have poorer outcomes, despite receiving the same clinical care. A significant improvement in overall population outcomes could be achieved if these socioeconomic differences, which may reflect the treatment compliance, could be eliminated

Analysis of Aurora kinase A expression in CD34+ blast cells isolated from patients with myelodysplastic syndromes and acute myeloid leukemia

Aurora kinase A, also known as aurora A, is a serine/threonine kinase that plays critical roles in mitosis entry, chromosome alignment, segregation, and cytokinesis. Overexpression of aurora A has been observed in many solid tumors and some hematopoietic neoplasms, but little is known about its expression in myeloid diseases. Because cytogenetic abnormalities play an essential role in the pathogenesis of myeloid malignancies, we hypothesized that aurora A deregulation may be involved in myelodysplastic syndromes and acute myeloid leukemia and contribute to the chromosomal instability observed in these diseases. We assessed aurora A mRNA levels in CD34+ bone marrow blasts from nine patients with acute myeloid leukemia, 20 patients with myelodysplastic syndromes, and five normal patients serving as controls. CD34+ blasts were isolated from bone marrow aspirate specimens using magnetic activated cell separation technology. RNA was extracted from purified CD34+ cells, and quantitative real-time reverse transcriptase polymerase chain reaction for aurora A was performed. Immunocytochemical analyses for total aurora A, phosphorylated aurora A, Ki-67, and activated caspase 3 were performed on cytospin slides made from purified CD34+ cells in myelodysplastic syndrome patients using standard methods. Aurora A mRNA and protein levels were correlated, as was aurora A mRNA level, with blast counts, cytogenetic abnormalities, and International Prognostic Scoring System score. We found that CD34+ cells in myelodysplastic syndromes and acute myeloid leukemia expressed aurora A at significantly higher levels (P = 0.01 and P = 0.01, respectively) than normal CD34+ cells. Aurora A mRNA levels correlated with total and phosphorylated protein levels (P = 0.0002 and P = 0.02, respectively). No significant correlation was found between aurora A mRNA level and blast count, blast viability, cytogenetic abnormalities, or the International Prognostic Scoring System score in patients with myelodysplastic syndromes. We conclude that aurora A is up-regulated in CD34+ blasts from myeloid neoplasms

In Vitro Transformation of Primary Human CD34+ Cells by AML Fusion Oncogenes: Early Gene Expression Profiling Reveals Possible Drug Target in AML

Different fusion oncogenes in acute myeloid leukemia (AML) have distinct clinical and laboratory features suggesting different modes of malignant transformation. Here we compare the in vitro effects of representatives of 4 major groups of AML fusion oncogenes on primary human CD34+ cells. As expected from their clinical similarities, MLL-AF9 and NUP98-HOXA9 had very similar effects in vitro. They both caused erythroid hyperplasia and a clear block in erythroid and myeloid maturation. On the other hand, AML1-ETO and PML-RARA had only modest effects on myeloid and erythroid differentiation. All oncogenes except PML-RARA caused a dramatic increase in long-term proliferation and self-renewal. Gene expression profiling revealed two distinct temporal patterns of gene deregulation. Gene deregulation by MLL-AF9 and NUP98-HOXA9 peaked 3 days after transduction. In contrast, the vast majority of gene deregulation by AML1-ETO and PML-RARA occurred within 6 hours, followed by a dramatic drop in the numbers of deregulated genes. Interestingly, the p53 inhibitor MDM2 was upregulated by AML1-ETO at 6 hours. Nutlin-3, an inhibitor of the interaction between MDM2 and p53, specifically inhibited the proliferation and self-renewal of primary human CD34+ cells transduced with AML1-ETO, suggesting that MDM2 upregulation plays a role in cell transformation by AML1-ETO. These data show that differences among AML fusion oncogenes can be recapitulated in vitro using primary human CD34+ cells and that early gene expression profiling in these cells can reveal potential drug targets in AML

The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans.

Histiocytic sarcoma (HS) is a rare malignant proliferation of histiocytes of uncertain molecular pathogenesis. Here, genetic analysis of coincident loss of Pten and Ink4a/Arf tumor suppressors in the mouse revealed a neoplastic phenotype dominated by a premalignant expansion of biphenotypic myelolymphoid cells followed by the development of HS. Pten protein loss occurred only in the histiocytic portion of tumors, suggesting a stepwise genetic inactivation in the generation of HS. Similarly, human HS showed genetic or epigenetic inactivation of PTEN, p16(INK4A), and p14(ARF), supporting the relevance of this genetically engineered mouse model of HS. These genetic and translational observations establish a cooperative role of Pten and Ink4a/Arf in the development of HS and provide mechanistic insights into the pathogenesis of human HS

Great Britain: the intertidal and underwater archaeology of Britain’s submerged landscapes

The submerged landscapes around Great Britain are extensive and would have offered productive territory for hunting, gathering, exploitation of aquatic and marine resources, and—in the final stages of postglacial sea-level rise—opportunities for agriculture. They would also have provided land connections to continental Europe and opportunities for communication by sea travel along now-submerged palaeocoastlines and river estuaries. Most of the archaeological material has been discovered in intertidal or shallow water conditions, but there are also discoveries in deeper water, with dates ranging from earliest human presence nearly one million years ago up to the establishment of modern sea level. Some later material is present where coastlines have continued to sink in more recent millennia. Intertidal sites are especially well represented because of relatively large tidal ranges and shallow offshore gradients on many coastlines. These are often associated with remains of submerged forests, which are periodically exposed at low tide and then covered up again by movements of sand. Some of the most distinctive intertidal finds are the human and animal footprints preserved in intertidal sediments in many locations, especially at Goldcliff East. The earliest, at Happisburgh, are dated between 0.78 and 1 Ma. Fully submerged sites include the Mesolithic site of Bouldnor Cliff with its worked timbers, and the Middle Stone Age artefacts from offshore aggregate Area 240 along with well-preserved ice age fauna and environmental indicators. Pioneering work using oil industry seismic records has produced detailed reconstructions of the submerged landscape, and this is being followed up by new work involving targeted acoustic survey and coring of sediments

Oligoclonal T cell receptor gene rearrangements in blood lymphocytes of patients with acute Epstein-Barr virus-induced infectious mononucleosis.

Gene rearrangement studies were performed on blood lymphocytes from eight patients with acute Epstein-Barr virus-induced infectious mononucleosis. The diagnosis in each case was based on characteristic clinical, hematologic, and serologic findings. The blood lymphocytes in each patient consisted predominantly of CD8+ T cells. EBV DNA was detected in seven patients by Southern blot analysis (EBV Bam HI W probe, Bam HI). A germline configuration was found for the immunoglobulin heavy and light chain genes (JH probe, Bam HI and Eco RI; C kappa probe, Bam HI; and C lambda probe, Eco RI). T cell receptor gene rearrangements were detected with J gamma and J beta 1 + 2 probes. Using a J gamma probe with two different restriction enzymes (Bgl II and Eco RI), the blood from each patient showed several bands corresponding to the polyclonal pattern previously described in the blood of normal individuals. Using J beta 1 + 2 probes with two different restriction enzymes (Bgl II and Bam HI), each case showed from 3 to about 12 extragermline bands of varying intensity and in different locations from case to case. In addition, each case showed relative deletion of the J beta 1 germline band. This oligoclonal pattern of T cell receptor gene rearrangements has not been previously reported in benign or malignant T cell populations